title: Interleukin-4 deficiency protects mice from acetaminophen-induced liver injury and inflammation by prevention of glutathione depletion.
abstract: OBJECTIVE
  Interleukin-4 (IL-4) is a multifunctional cytokine involved in many diseases such as autoimmune hepatitis and idiosyncratic drug reactions. However, its role in acetaminophen (APAP)-induced liver injury remains unclear. Our objective was to evaluate the contribution of IL-4 to the pathogenesis of APAP-induced liver injury.
  
  
  METHODS
  Balb/C (WT) and IL-4 knockout (IL-4(-/-)) mice were orally overdosed with APAP. After 24 h, survival percentage, biochemical and morphological markers of liver injury, and tissue inflammation were assessed.
  
  
  RESULTS
  IL-4(-/-) mice were protected from APAP toxicity. Intravital confocal microscopy, tissue histology and serum ALT levels showed significantly less liver injury and inflammation than in the WT group, which may explain the increased survival rate of IL-4(-/-) mice. In addition, IL-4(-/-) mice had decreased production of tumor necrosis factor α, CXCL1 and interleukin-1β in the liver, but not in a remote site such as the lungs. Hepatic macrophage activation was markedly reduced in IL-4-deficient mice. In addition, glutathione depletion-a primary cause of APAP-mediated injury-was significantly attenuated in IL-4(-/-) mice.
  
  
  CONCLUSIONS
  Taken together, our data demonstrate that IL-4(-/-) mice are protected from APAP-induced liver injury due to reduced depletion of glutathione, which prevented liver damage and tissue inflammation.
authors.affiliation: Laboratório de Imunobiofotônica, Departamento de Morfologia, ICB, Universidade Federal de Minas Gerais, Av. Antonio Carlos, Pampulha, Belo Horizonte, MG, 6627, Brazil.
authors.forename: Daniele Araújo
authors.initials: DA
authors.lastname: Pires
authors.forename: Pedro Elias
authors.initials: PE
authors.lastname: Marques
authors.forename: Rafaela Vaz
authors.initials: RV
authors.lastname: Pereira
authors.forename: Bruna Araújo
authors.initials: BA
authors.lastname: David
authors.forename: Lindisley Ferreira
authors.initials: LF
authors.lastname: Gomides
authors.forename: Ana Carolina Fialho
authors.initials: AC
authors.lastname: Dias
authors.forename: Albená
authors.initials: A
authors.lastname: Nunes-Silva
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
authors.forename: Denise Carmona
authors.initials: DC
authors.lastname: Cara
authors.forename: Leda Quercia
authors.initials: LQ
authors.lastname: Vieira
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Gustavo Batista
authors.initials: GB
authors.lastname: Menezes
mesh_terms: D000082:Acetaminophen; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D054360:Chemokine CXCL1 / Q000276:immunology; D005978:Glutathione / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D000082:Acetaminophen; D005978:Glutathione